Is CLCN6 p.Cys17Ser (c.49T>A) pathogenic?

CLCN6 p.Cys17Ser (c.49T>A) is classified Uncertain significance in CLCN6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-29). AlphaMissense: likely benign (0.2478); Absent from gnomAD v4.1.

How common is CLCN6 p.Cys17Ser (c.49T>A) in the general population?

CLCN6 p.Cys17Ser (c.49T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLCN6 p.Cys17Ser (c.49T>A)?

AlphaMissense predicts likely benign (score 0.2478) — an in-silico prediction, not a clinical call.

CLCN6 p.Cys17Ser

c.49T>A · rs2523015203 · VCV2739643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2478 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2478	likely benign
REVEL	0.514	indeterminate
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 34 kb · p 2.8e-06 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN6
Protein: p.Cys17Ser
Coding: c.49T>A
MANE Select: NM_001286
dbSNP: rs2523015203
Type: single nucleotide variant
Location: chr1:11806311 (GRCh38)
Gene constraint: LOEUF 0.787 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.43 · 3 PDB

Full CLCN6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLCN6 p.Tyr553Cys Pathogenic ★★ ⚠ same type
CLCN6 p.Ala127Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala144Glu Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala256Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala392Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala522Thr Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala527Val Uncertain significance ★★ ⚠ same type
CLCN6 p.Ala78Val Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/clcn6-p-cys17ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown